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An engineered multicellular stem cell niche for the 3D derivation of human myogenic progenitors from iPSCs. EMBO J. (IF 11.598) Pub Date : 2022-06-15 Omid Mashinchian,Filippo De Franceschi,Sina Nassiri,Joris Michaud,Eugenia Migliavacca,Patrick Aouad,Sylviane Metairon,Solenn Pruvost,Sonia Karaz,Paul Fabre,Thomas Molina,Pascal Stuelsatz,Nagabhooshan Hegde,Emmeran Le Moal,Gabriele Dammone,Nicolas A Dumont,Matthias P Lutolf,Jerome N Feige,C Florian Bentzinger
Fate decisions in the embryo are controlled by a plethora of microenvironmental interactions in a three-dimensional niche. To investigate whether aspects of this microenvironmental complexity can be engineered to direct myogenic human-induced pluripotent stem cell (hiPSC) differentiation, we here screened murine cell types present in the developmental or adult stem cell niche in heterotypic suspension
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Nucleome programming is required for the foundation of totipotency in mammalian germline development. EMBO J. (IF 11.598) Pub Date : 2022-06-15 Masahiro Nagano,Bo Hu,Shihori Yokobayashi,Akitoshi Yamamura,Fumiya Umemura,Mariel Coradin,Hiroshi Ohta,Yukihiro Yabuta,Yukiko Ishikura,Ikuhiro Okamoto,Hiroki Ikeda,Naofumi Kawahira,Yoshiaki Nosaka,Sakura Shimizu,Yoji Kojima,Ken Mizuta,Tomoko Kasahara,Yusuke Imoto,Killian Meehan,Roman Stocsits,Gordana Wutz,Yasuaki Hiraoka,Yasuhiro Murakawa,Takuya Yamamoto,Kikue Tachibana,Jan-Michel Peters,Leonid A Mirny
Germ cells are unique in engendering totipotency, yet the mechanisms underlying this capacity remain elusive. Here, we perform comprehensive and in-depth nucleome analysis of mouse germ-cell development in vitro, encompassing pluripotent precursors, primordial germ cells (PGCs) before and after epigenetic reprogramming, and spermatogonia/spermatogonial stem cells (SSCs). Although epigenetic reprogramming
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The Hippo pathway drives the cellular response to hydrostatic pressure. EMBO J. (IF 11.598) Pub Date : 2022-06-15 Jiwon Park,Siyang Jia,Donald Salter,Pierre Bagnaninchi,Carsten G Hansen
Cells need to rapidly and precisely react to multiple mechanical and chemical stimuli in order to ensure precise context-dependent responses. This requires dynamic cellular signalling events that ensure homeostasis and plasticity when needed. A less well-understood process is cellular response to elevated interstitial fluid pressure, where the cell senses and responds to changes in extracellular hydrostatic
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A multifunctional locus controls motor neuron differentiation through short and long noncoding RNAs. EMBO J. (IF 11.598) Pub Date : 2022-06-13 Andrea Carvelli,Adriano Setti,Fabio Desideri,Silvia Giulia Galfrè,Silvia Biscarini,Tiziana Santini,Alessio Colantoni,Giovanna Peruzzi,Matteo Jacopo Marzi,Davide Capauto,Silvia Di Angelantonio,Monica Ballarino,Francesco Nicassio,Pietro Laneve,Irene Bozzoni
The transition from dividing progenitors to postmitotic motor neurons (MNs) is orchestrated by a series of events, which are mainly studied at the transcriptional level by analyzing the activity of specific programming transcription factors. Here, we identify a post-transcriptional role of a MN-specific transcriptional unit (MN2) harboring a lncRNA (lncMN2-203) and two miRNAs (miR-325-3p and miR-384-5p)
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Chemogenetic profiling reveals PP2A-independent cytotoxicity of proposed PP2A activators iHAP1 and DT-061. EMBO J. (IF 11.598) Pub Date : 2022-06-13 Gianmatteo Vit,Joana Duro,Girish Rajendraprasad,Emil P T Hertz,Lya Katrine Kauffeldt Holland,Melanie Bianca Weisser,Brennan C McEwan,Blanca Lopez-Mendez,Paula Sotelo-Parrilla,A Arockia Jeyaprakash,Guillermo Montoya,Niels Mailand,Kenji Maeda,Arminja Kettenbach,Marin Barisic,Jakob Nilsson
Protein phosphatase 2A (PP2A) is an abundant phosphoprotein phosphatase that acts as a tumor suppressor. For this reason, compounds able to activate PP2A are attractive anticancer agents. The compounds iHAP1 and DT-061 have recently been reported to selectively stabilize specific PP2A-B56 complexes to mediate cell killing. We were unable to detect direct effects of iHAP1 and DT-061 on PP2A-B56 activity
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Characterization of naked mole-rat hematopoiesis reveals unique stem and progenitor cell patterns and neotenic traits. EMBO J. (IF 11.598) Pub Date : 2022-06-13 Stephan Emmrich,Alexandre Trapp,Frances Tolibzoda Zakusilo,Maggie E Straight,Albert K Ying,Alexander Tyshkovskiy,Marco Mariotti,Spencer Gray,Zhihui Zhang,Michael G Drage,Masaki Takasugi,Jan-Henning Klusmann,Vadim N Gladyshev,Andrei Seluanov,Vera Gorbunova
Naked mole rats (NMRs) are the longest-lived rodents yet their stem cell characteristics remain enigmatic. Here, we comprehensively mapped the NMR hematopoietic landscape and identified unique features likely contributing to longevity. Adult NMRs form red blood cells in spleen and marrow, which comprise a myeloid bias toward granulopoiesis together with decreased B-lymphopoiesis. Remarkably, youthful
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Feeding activates FGF15-SHP-TFEB-mediated lipophagy in the gut. EMBO J. (IF 11.598) Pub Date : 2022-06-10 Sunmi Seok,Young-Chae Kim,Yang Zhang,Bo Kong,Grace Guo,Jian Ma,Byron Kemper,Jongsook Kim Kemper
Lysosome-mediated macroautophagy, including lipophagy, is activated under nutrient deprivation but is repressed after feeding. We show that, unexpectedly, feeding activates intestinal autophagy/lipophagy in a manner dependent on both the orphan nuclear receptor, small heterodimer partner (SHP/NR0B2), and the gut hormone, fibroblast growth factor-15/19 (FGF15/19). Furthermore, postprandial intestinal
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Centrosome function is critical during terminal erythroid differentiation. EMBO J. (IF 11.598) Pub Date : 2022-06-09 Péter Tátrai,Fanni Gergely
Red blood cells are produced by terminal erythroid differentiation, which involves the dramatic morphological transformation of erythroblasts into enucleated reticulocytes. Microtubules are important for enucleation, but it is not known if the centrosome, a key microtubule-organizing center, is required as well. Mice lacking the conserved centrosome component, CDK5RAP2, are likely to have defective
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Arabidopsis HEAT SHOCK FACTOR BINDING PROTEIN is required to limit meiotic crossovers and HEI10 transcription. EMBO J. (IF 11.598) Pub Date : 2022-06-07 Juhyun Kim,Jihye Park,Heejin Kim,Namil Son,Eun-Jung Kim,Jaeil Kim,Dohwan Byun,Youngkyung Lee,Yeong Mi Park,Divyashree C Nageswaran,Pallas Kuo,Teresa Rose,Tuong Vi T Dang,Ildoo Hwang,Christophe Lambing,Ian R Henderson,Kyuha Choi
The number of meiotic crossovers is tightly controlled and most depend on pro-crossover ZMM proteins, such as the E3 ligase HEI10. Despite the importance of HEI10 dosage for crossover formation, how HEI10 transcription is controlled remains unexplored. In a forward genetic screen using a fluorescent crossover reporter in Arabidopsis thaliana, we identify heat shock factor binding protein (HSBP) as
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TRIM27 cooperates with STK38L to inhibit ULK1-mediated autophagy and promote tumorigenesis. EMBO J. (IF 11.598) Pub Date : 2022-06-07 Yi Yang,Yifu Zhu,Shuai Zhou,Peipei Tang,Ran Xu,Yuwei Zhang,Dongping Wei,Jian Wen,Rick F Thorne,Xu Dong Zhang,Jun-Lin Guan,Lianxin Liu,Mian Wu,Song Chen
Autophagy represents a fundamental mechanism for maintaining cell survival and tissue homeostasis in response to physiological and pathological stress. Autophagy initiation converges on the FIP200-ATG13-ULK1 complex wherein the serine/threonine kinase ULK1 plays a central role. Here, we reveal that the E3 ubiquitin ligase TRIM27 functions as a negative regulatory component of the FIP200-ATG13-ULK1
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Palmitoylation of γb protein directs a dynamic switch between Barley stripe mosaic virus replication and movement. EMBO J. (IF 11.598) Pub Date : 2022-06-01 Ning Yue,Zhihao Jiang,Xuan Zhang,Zhenggang Li,Xueting Wang,Zhiyan Wen,Zongyu Gao,Qinglin Pi,Yongliang Zhang,Xian-Bing Wang,Chenggui Han,Jialin Yu,Dawei Li
Viral replication and movement are intimately linked; however, the molecular mechanisms regulating the transition between replication and subsequent movement remain largely unknown. We previously demonstrated that the Barley stripe mosaic virus (BSMV) γb protein promotes viral replication and movement by interacting with the αa replicase and TGB1 movement proteins. Here, we found that γb is palmitoylated
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Disulfiram bolsters T-cell anti-tumor immunity through direct activation of LCK-mediated TCR signaling. EMBO J. (IF 11.598) Pub Date : 2022-05-31 Qinlan Wang,Ting Zhu,Naijun Miao,Yingying Qu,Zhuning Wang,Yinong Chao,Jing Wang,Wei Wu,Xinyi Xu,Chenqi Xu,Li Xia,Feng Wang
Activation of the T-cell antigen receptor (TCR)-CD3 complex is critical to induce the anti-tumor response of CD8+ T cells. Here, we found that disulfiram (DSF), an FDA-approved drug previously used to treat alcohol dependency, directly activates TCR signaling. Mechanistically, DSF covalently binds to Cys20/Cys23 residues of lymphocyte-specific protein tyrosine kinase (LCK) and enhances its tyrosine
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Subcellular localization of Type VI secretion system assembly in response to cell-cell contact. EMBO J. (IF 11.598) Pub Date : 2022-05-30 Lin Lin,Raffaella Capozzoli,Alexia Ferrand,Miro Plum,Andrea Vettiger,Marek Basler
Bacteria require a number of systems, including the type VI secretion system (T6SS), for interbacterial competition and pathogenesis. The T6SS is a large nanomachine that can deliver toxins directly across membranes of proximal target cells. Since major reassembly of T6SS is necessary after each secretion event, accurate timing and localization of T6SS assembly can lower the cost of protein translocation
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Stress-induced vesicular assemblies of dual leucine zipper kinase are signaling hubs involved in kinase activation and neurodegeneration. EMBO J. (IF 11.598) Pub Date : 2022-05-25 Elena Tortosa,Arundhati Sengupta Ghosh,Qingling Li,Weng Ruh Wong,Trent Hinkle,Wendy Sandoval,Christopher M Rose,Casper C Hoogenraad
Mitogen-activated protein kinases (MAPKs) drive key signaling cascades during neuronal survival and degeneration. The localization of kinases to specific subcellular compartments is a critical mechanism to locally control signaling activity and specificity upon stimulation. However, how MAPK signaling components tightly control their localization remains largely unknown. Here, we systematically analyzed
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Controlled X-chromosome dynamics defines meiotic potential of female mouse in vitro germ cells. EMBO J. (IF 11.598) Pub Date : 2022-05-23 Jacqueline Severino,Moritz Bauer,Tom Mattimoe,Niccolò Arecco,Luca Cozzuto,Patricia Lorden,Norio Hamada,Yoshiaki Nosaka,So I Nagaoka,Pauline Audergon,Antonio Tarruell,Holger Heyn,Katsuhiko Hayashi,Mitinori Saitou,Bernhard Payer
The mammalian germline is characterized by extensive epigenetic reprogramming during its development into functional eggs and sperm. Specifically, the epigenome requires resetting before parental marks can be established and transmitted to the next generation. In the female germline, X-chromosome inactivation and reactivation are among the most prominent epigenetic reprogramming events, yet very little
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Structural insights into ClpP protease side exit pore-opening by a pH drop coupled with substrate hydrolysis. EMBO J. (IF 11.598) Pub Date : 2022-05-20 Leehyeon Kim,Byung-Gil Lee,Minki Kim,Min Kyung Kim,Do Hoon Kwon,Hyunmin Kim,Heike Brötz-Oesterhelt,Soung-Hun Roh,Hyun Kyu Song
The ClpP serine peptidase is a tetradecameric degradation molecular machine involved in many physiological processes. It becomes a competent ATP-dependent protease when coupled with Clp-ATPases. Small chemical compounds, acyldepsipeptides (ADEPs), are known to cause the dysregulation and activation of ClpP without ATPases and have potential as novel antibiotics. Previously, structural studies of ClpP
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Tau: a phase in the crowd. EMBO J. (IF 11.598) Pub Date : 2022-05-17 Vera I Wiersma,Ruben Rigort,Magdalini Polymenidou
From the management of microtubules to the production of pathological species: liquid-liquid phase separation may tune the behavior of the protein tau in health and neurodegenerative disease. In this issue of The EMBO Journal, Hochmair et al (2022) demystify important aspects of tau condensate compilation.
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Autophagy power expands: fuse those cells! EMBO J. (IF 11.598) Pub Date : 2022-05-13 Rojyar Khezri,Tor Erik Rusten
The lysosomal degradation pathway of autophagy depends on a set of evolutionarily conserved autophagy-related molecules (ATGs) bestowed with the power to direct membrane trafficking and biology. In this issue of EMBO Journal, Kakanj P et al reveal a surprising role for the autophagy machinery in cell fusion (Kakanj et al, 2022). Autophagy is physiologically required for cell syncytium formation through
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The multifaceted role of autophagy in cancer. EMBO J. (IF 11.598) Pub Date : 2022-05-10 Ryan C Russell,Kun-Liang Guan
Autophagy is a cellular degradative pathway that plays diverse roles in maintaining cellular homeostasis. Cellular stress caused by starvation, organelle damage, or proteotoxic aggregates can increase autophagy, which uses the degradative capacity of lysosomal enzymes to mitigate intracellular stresses. Early studies have shown a role for autophagy in the suppression of tumorigenesis. However, work
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Host succinate inhibits influenza virus infection through succinylation and nuclear retention of the viral nucleoprotein. EMBO J. (IF 11.598) Pub Date : 2022-05-04 Antoine Guillon,Deborah Brea-Diakite,Adeline Cezard,Alan Wacquiez,Thomas Baranek,Jérôme Bourgeais,Frédéric Picou,Virginie Vasseur,Léa Meyer,Christophe Chevalier,Adrien Auvet,José M Carballido,Lydie Nadal Desbarats,Florent Dingli,Andrei Turtoi,Audrey Le Gouellec,Florence Fauvelle,Amélie Donchet,Thibaut Crépin,Pieter S Hiemstra,Christophe Paget,Damarys Loew,Olivier Herault,Nadia Naffakh,Ronan Le Goffic
Influenza virus infection causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic signaling during infection may help to design innovative antiviral approaches. Using bronchoalveolar lavages of infected mice, we here demonstrate that influenza virus induces a major reprogramming of lung metabolism. We focused on mitochondria-derived
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Toll-like receptors matter: plasmacytoid dendritic cells in COVID-19. EMBO J. (IF 11.598) Pub Date : 2022-04-26 Jennifer Becker,Ulrich Kalinke
Plasmacytoid dendritic cells (pDC) have the unique ability to rapidly mount high-level antiviral type I interferon (IFN-I) responses during diverse virus infections. In COVID-19 patients, reduced pDC numbers correlate with diminished IFN-I serum levels and enhanced disease severity. However, the molecular mechanisms underlying SARS-CoV-2-mediated pDC stimulation to induce cytokine responses are still
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Mammalian antiviral RNAi is on the move. EMBO J. (IF 11.598) Pub Date : 2022-04-26 Kristina L Schierhorn,Raul Y Sanchez-David,Pierre V Maillard
Recent work reported the existence of a mammalian cell-autonomous antiviral defence based on RNA interference (RNAi), which relies on the accumulation of virus-derived small interfering RNAs (vsiRNAs) to guide the degradation of complementary viral RNAs. In a new study, Zhang et al (2022) find that, in infected mice, vsiRNAs can enter the bloodstream via their incorporation into extracellular vesicles
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C-terminal deletion-induced condensation sequesters AID from IgH targets in immunodeficiency. EMBO J. (IF 11.598) Pub Date : 2022-04-26 Xia Xie,Tingting Gan,Bing Rao,Weiwei Zhang,Rohit A Panchakshari,Dingpeng Yang,Xiong Ji,Yu Cao,Frederick W Alt,Fei-Long Meng,Jiazhi Hu
In activated B cells, activation-induced cytidine deaminase (AID) generates programmed DNA lesions required for antibody class switch recombination (CSR), which may also threaten genome integrity. AID dynamically shuttles between cytoplasm and nucleus, and the majority stays in the cytoplasm due to active nuclear export mediated by its C-terminal peptide. In immunodeficient-patient cells expressing
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CROP: a retromer‐PROPPIN complex mediating membrane fission in the endo‐lysosomal system EMBO J. (IF 11.598) Pub Date : 2022-04-25 Thibault Courtellemont,Maria Giovanna De Leo,Navin Gopaldass,Andreas Mayer
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c-Maf enforces cytokine production and promotes memory-like responses in mouse and human type 2 innate lymphoid cells. EMBO J. (IF 11.598) Pub Date : 2022-04-25 Sara Trabanelli,Giuseppe Ercolano,Tania Wyss,Alejandra Gomez-Cadena,Maryline Falquet,Daniela Cropp,Claire Imbratta,Marine M Leblond,Valentina Salvestrini,Antonio Curti,Olivier Adotevi,Camilla Jandus,Grégory Verdeil
Group-2 innate lymphoid cells (ILC2s), which are involved in type 2 inflammatory diseases such as allergy, can exhibit immunological memory, but the basis of this ILC2 "trained immunity" has remained unclear. Here, we found that stimulation with IL-33/IL-25 or exposure to the allergen papain induces the expression of the transcription factor c-Maf in mouse ILC2s. Chronic papain exposure results in
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Cellular responses to halofuginone reveal a vulnerability of the GCN2 branch of the integrated stress response. EMBO J. (IF 11.598) Pub Date : 2022-04-25 Aleksandra P Pitera,Maria Szaruga,Sew-Yeu Peak-Chew,Steven W Wingett,Anne Bertolotti
Halofuginone (HF) is a phase 2 clinical compound that inhibits the glutamyl-prolyl-tRNA synthetase (EPRS) thereby inducing the integrated stress response (ISR). Here, we report that halofuginone indeed triggers the predicted canonical ISR adaptations, consisting of attenuation of protein synthesis and gene expression reprogramming. However, the former is surprisingly atypical and occurs to a similar
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Atossa: a royal link between OXPHOS metabolism and macrophage migration. EMBO J. (IF 11.598) Pub Date : 2022-04-25 Pedro Latorre-Muro,Pere Puigserver
The ability of immune cells to penetrate affected tissues is highly dependent on energy provided by mitochondria, yet their involvement in promoting migration remains unclear. Recent work by Emtenani et al (2022) describes a nuclear Atossa-Porthos axis that adjusts transcription and translation of a small subset of OXPHOS genes to increase mitochondrial bioenergetics and allow macrophage tissue invasion
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Astrogenesis in the murine dentate gyrus is a life-long and dynamic process. EMBO J. (IF 11.598) Pub Date : 2022-04-22 Julia Schneider,Johannes Weigel,Marie-Theres Wittmann,Pavel Svehla,Sebastian Ehrt,Fang Zheng,Tarek Elmzzahi,Julian Karpf,Lucía Paniagua-Herranz,Onur Basak,Arif Ekici,Andre Reis,Christian Alzheimer,Felipe Ortega de la O,Sabine Liebscher,Ruth Beckervordersandforth
Astrocytes are highly abundant in the mammalian brain, and their functions are of vital importance for all aspects of development, adaption, and aging of the central nervous system (CNS). Mounting evidence indicates the important contributions of astrocytes to a wide range of neuropathies. Still, our understanding of astrocyte development significantly lags behind that of other CNS cells. We here combine
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Mammalian UPF3A and UPF3B can activate nonsense-mediated mRNA decay independently of their exon junction complex binding. EMBO J. (IF 11.598) Pub Date : 2022-04-22 Zhongxia Yi,René M Arvola,Sean Myers,Corinne N Dilsavor,Rabab Abu Alhasan,Bayley N Carter,Robert D Patton,Ralf Bundschuh,Guramrit Singh
Nonsense-mediated mRNA decay (NMD) is governed by the three conserved factors-UPF1, UPF2, and UPF3. While all three are required for NMD in yeast, UPF3B is dispensable for NMD in mammals, and its paralog UPF3A is suggested to only weakly activate or even repress NMD due to its weaker binding to the exon junction complex (EJC). Here, we characterize the UPF3A/B-dependence of NMD in human cell lines
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The goodies of chelated fat: iron-regulated lipid droplet biogenesis precedes and preserves mitophagy. EMBO J. (IF 11.598) Pub Date : 2022-04-22 Marc Liesa
The role of iron-regulated mitophagy in lipid metabolism is unclear. Recent work by Long, Sanchez-Martinez et al (2022) shows that iron chelation induces a primary change in lipid metabolism that promotes fat accumulation and precedes mitophagy.
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TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis. EMBO J. (IF 11.598) Pub Date : 2022-04-22 Qichao Huang,Dan Wu,Jing Zhao,Zeyu Yan,Lin Chen,Shanshan Guo,Dalin Wang,Chong Yuan,Yinping Wang,Xiaoli Liu,Jinliang Xing
The mechanisms underlying cancer metastasis remain poorly understood. Here, we report that TFAM deficiency rapidly and stably induced spontaneous lung metastasis in mice with liver cancer. Interestingly, unexpected polymerization of nuclear actin was observed in TFAM-knockdown HCC cells when cytoskeleton was examined. Polymerization of nuclear actin is causally linked to the high-metastatic ability
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Human UPF3A and UPF3B enable fault-tolerant activation of nonsense-mediated mRNA decay. EMBO J. (IF 11.598) Pub Date : 2022-04-22 Damaris Wallmeroth,Jan-Wilm Lackmann,Sabrina Kueckelmann,Janine Altmüller,Christoph Dieterich,Volker Boehm,Niels H Gehring
The paralogous human proteins UPF3A and UPF3B are involved in recognizing mRNAs targeted by nonsense-mediated mRNA decay (NMD). UPF3B has been demonstrated to support NMD, presumably by bridging an exon junction complex (EJC) to the NMD factor UPF2. The role of UPF3A has been described either as a weak NMD activator or an NMD inhibitor. Here, we present a comprehensive functional analysis of UPF3A
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The blood–brain barrier—a metabolic ecosystem EMBO J. (IF 11.598) Pub Date : 2022-04-19 Marco Castro,Michael Potente
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ZDHHC18 negatively regulates cGAS-mediated innate immunity through palmitoylation. EMBO J. (IF 11.598) Pub Date : 2022-04-19 Chengrui Shi,Xikang Yang,Ye Liu,Hongpeng Li,Huiying Chu,Guohui Li,Hang Yin
Double-stranded DNA is recognized as a danger signal by cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS), triggering innate immune responses. Palmitoylation is an important post-translational modification (PTM) catalyzed by DHHC-palmitoyl transferases, which participate in the regulation of diverse biological processes. However, whether palmitoylation regulates cGAS function has
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The intrinsically disordered CARDs-Helicase linker in RIG-I is a molecular gate for RNA proofreading. EMBO J. (IF 11.598) Pub Date : 2022-04-19 Brandon D Schweibenz,Swapnil C Devarkar,Mihai Solotchi,Candice Craig,Jie Zheng,Bruce D Pascal,Samantha Gokhale,Ping Xie,Patrick R Griffin,Smita S Patel
The innate immune receptor RIG-I provides a first line of defense against viral infections. Viral RNAs are recognized by RIG-I's C-terminal domain (CTD), but the RNA must engage the helicase domain to release the signaling CARD (Caspase Activation and Recruitment Domain) domains from their autoinhibitory CARD2:Hel2i interactions. Because the helicase itself lacks RNA specificity, mechanisms to proofread
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DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion. EMBO J. (IF 11.598) Pub Date : 2022-04-12 Maeve Long,Alvaro Sanchez-Martinez,Marianna Longo,Fumi Suomi,Hans Stenlund,Annika I Johansson,Homa Ehsan,Veijo T Salo,Lambert Montava-Garriga,Seyedehshima Naddafi,Elina Ikonen,Ian G Ganley,Alexander J Whitworth,Thomas G McWilliams
Mitophagy removes defective mitochondria via lysosomal elimination. Increased mitophagy coincides with metabolic reprogramming, yet it remains unknown whether mitophagy is a cause or consequence of such state changes. The signalling pathways that integrate with mitophagy to sustain cell and tissue integrity also remain poorly defined. We performed temporal metabolomics on mammalian cells treated with
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An alternative UPF1 isoform drives conditional remodeling of nonsense‐mediated mRNA decay EMBO J. (IF 11.598) Pub Date : 2022-04-11 Sarah E Fritz,Soumya Ranganathan,Clara D Wang,J Robert Hogg
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3D imaging for driving cancer discovery. EMBO J. (IF 11.598) Pub Date : 2022-04-11 Ravian L van Ineveld,Esmée J van Vliet,Ellen J Wehrens,Maria Alieva,Anne C Rios
Our understanding of the cellular composition and architecture of cancer has primarily advanced using 2D models and thin slice samples. This has granted spatial information on fundamental cancer biology and treatment response. However, tissues contain a variety of interconnected cells with different functional states and shapes, and this complex organization is impossible to capture in a single plane
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Structure of the RZZ complex and molecular basis of Spindly‐driven corona assembly at human kinetochores EMBO J. (IF 11.598) Pub Date : 2022-04-04 Tobias Raisch,Giuseppe Ciossani,Ennio d’Amico,Verena Cmentowski,Sara Carmignani,Stefano Maffini,Felipe Merino,Sabine Wohlgemuth,Ingrid R Vetter,Stefan Raunser,Andrea Musacchio
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A thermodynamic switch modulates abscisic acid receptor sensitivity EMBO J. (IF 11.598) Pub Date : 2022-04-04 Florine Dupeux,Julia Santiago,Katja Betz,Jamie Twycross,Sang‐Youl Park,Lesia Rodriguez,Miguel Gonzalez‐Guzman,Malene Rinkjøbing Jensen,Natalio Krasnogor,Martin Blackledge,Michael Holdsworth,Sean R Cutler,Pedro L Rodriguez,José Antonio Márquez
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RNA is required for the integrity of multiple nuclear and cytoplasmic membrane-less RNP granules. EMBO J. (IF 11.598) Pub Date : 2022-03-31 Carolyn J Decker,James M Burke,Patrick K Mulvaney,Roy Parker
Numerous membrane-less organelles, composed of a combination of RNA and proteins, are observed in the nucleus and cytoplasm of eukaryotic cells. These RNP granules include stress granules (SGs), processing bodies (PBs), Cajal bodies, and nuclear speckles. An unresolved question is how frequently RNA molecules are required for the integrity of RNP granules in either the nucleus or cytosol. To address
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K27-linked ubiquitylation promotes p97 substrate processing and is essential for cell proliferation. EMBO J. (IF 11.598) Pub Date : 2022-03-29 Robert F Shearer,Dimitris Typas,Fabian Coscia,Sofie Schovsbo,Thomas Kruse,Andreas Mund,Niels Mailand
Conjugation of ubiquitin (Ub) to numerous substrate proteins regulates virtually all cellular processes. Eight distinct ubiquitin polymer linkages specifying different functional outcomes are generated in cells. However, the roles of some atypical poly-ubiquitin topologies, in particular linkages via lysine 27 (K27), remain poorly understood due to a lack of tools for their specific detection and manipulation
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Mouse circulating extracellular vesicles contain virus-derived siRNAs active in antiviral immunity. EMBO J. (IF 11.598) Pub Date : 2022-03-28 Yuqiang Zhang,Yunpeng Dai,Jiaxin Wang,Yan Xu,Zhe Li,Jinfeng Lu,Yongfen Xu,Jin Zhong,Shou-Wei Ding,Yang Li
Induction and suppression of antiviral RNA interference (RNAi) has been observed in mammals during infection with at least seven distinct RNA viruses, including some that are pathogenic in humans. However, while the cell-autonomous immune response mediated by antiviral RNAi is gradually being recognized, little is known about systemic antiviral RNAi in mammals. Furthermore, extracellular vesicles (EVs)
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Macrophage mitochondrial bioenergetics and tissue invasion are boosted by an Atossa-Porthos axis in Drosophila. EMBO J. (IF 11.598) Pub Date : 2022-03-23 Shamsi Emtenani,Elliot T Martin,Attila Gyoergy,Julia Bicher,Jakob-Wendelin Genger,Thomas Köcher,Maria Akhmanova,Mariana Guarda,Marko Roblek,Andreas Bergthaler,Thomas R Hurd,Prashanth Rangan,Daria E Siekhaus
Cellular metabolism must adapt to changing demands to enable homeostasis. During immune responses or cancer metastasis, cells leading migration into challenging environments require an energy boost, but what controls this capacity is unclear. Here, we study a previously uncharacterized nuclear protein, Atossa (encoded by CG9005), which supports macrophage invasion into the germband of Drosophila by
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Endosomal phosphatidylinositol 3-phosphate controls synaptic vesicle cycling and neurotransmission. EMBO J. (IF 11.598) Pub Date : 2022-03-22 Guan-Ting Liu,Gaga Kochlamazashvili,Dmytro Puchkov,Rainer Müller,Carsten Schultz,Albert I Mackintosh,Dennis Vollweiter,Volker Haucke,Tolga Soykan
Neural circuit function requires mechanisms for controlling neurotransmitter release and the activity of neuronal networks, including modulation by synaptic contacts, synaptic plasticity, and homeostatic scaling. However, how neurons intrinsically monitor and feedback control presynaptic neurotransmitter release and synaptic vesicle (SV) recycling to restrict neuronal network activity remains poorly
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Protein synthesis control in cancer: selectivity and therapeutic targeting. EMBO J. (IF 11.598) Pub Date : 2022-03-22 Joanna R Kovalski,Duygu Kuzuoglu-Ozturk,Davide Ruggero
Translational control of mRNAs is a point of convergence for many oncogenic signals through which cancer cells tune protein expression in tumorigenesis. Cancer cells rely on translational control to appropriately adapt to limited resources while maintaining cell growth and survival, which creates a selective therapeutic window compared to non-transformed cells. In this review, we first discuss how
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Hyperphosphorylation tunes TDP‐43 solubility EMBO J. (IF 11.598) Pub Date : 2022-03-21 Garrett M Ginell,Alex S Holehouse
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Ketogenic HMG-CoA lyase and its product β-hydroxybutyrate promote pancreatic cancer progression. EMBO J. (IF 11.598) Pub Date : 2022-03-21 Victoire Gouirand,Tristan Gicquel,Evan C Lien,Emilie Jaune-Pons,Quentin Da Costa,Pascal Finetti,Elodie Metay,Camille Duluc,Jared R Mayers,Stephane Audebert,Luc Camoin,Laurence Borge,Marion Rubis,Julie Leca,Jeremy Nigri,François Bertucci,Nelson Dusetti,Juan L Iovanna,Richard Tomasini,Ghislain Bidaut,Fabienne Guillaumond,Matthew G Vander Heiden,Sophie Vasseur
Pancreatic ductal adenocarcinoma (PDA) tumor cells are deprived of oxygen and nutrients and therefore must adapt their metabolism to ensure proliferation. In some physiological states, cells rely on ketone bodies to satisfy their metabolic needs, especially during nutrient stress. Here, we show that PDA cells can activate ketone body metabolism and that β-hydroxybutyrate (βOHB) is an alternative cell-intrinsic
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Novel transient cytoplasmic rings stabilize assembling bacterial flagellar motors. EMBO J. (IF 11.598) Pub Date : 2022-03-18 Mohammed Kaplan,Catherine M Oikonomou,Cecily R Wood,Georges Chreifi,Poorna Subramanian,Davi R Ortega,Yi-Wei Chang,Morgan Beeby,Carrie L Shaffer,Grant J Jensen
The process by which bacterial cells build their intricate flagellar motility apparatuses has long fascinated scientists. Our understanding of this process comes mainly from studies of purified flagella from two species, Escherichia coli and Salmonella enterica. Here, we used electron cryo-tomography (cryo-ET) to image the assembly of the flagellar motor in situ in diverse Proteobacteria: Hylemonella
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Molecular crowding and RNA synergize to promote phase separation, microtubule interaction, and seeding of Tau condensates. EMBO J. (IF 11.598) Pub Date : 2022-03-17 Janine Hochmair,Christian Exner,Maximilian Franck,Alvaro Dominguez-Baquero,Lisa Diez,Hévila Brognaro,Matthew L Kraushar,Thorsten Mielke,Helena Radbruch,Senthilvelrajan Kaniyappan,Sven Falke,Eckhard Mandelkow,Christian Betzel,Susanne Wegmann
Biomolecular condensation of the neuronal microtubule-associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation with RNA, two conditions likely coexisting in the cytosol
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Airway secretory cell fate conversion via YAP-mTORC1-dependent essential amino acid metabolism. EMBO J. (IF 11.598) Pub Date : 2022-03-14 Hae Yon Jeon,Jinwook Choi,Lianne Kraaier,Young Hoon Kim,David Eisenbarth,Kijong Yi,Ju-Gyeong Kang,Jin Woo Kim,Hyo Sup Shim,Joo-Hyeon Lee,Dae-Sik Lim
Tissue homeostasis requires lineage fidelity of stem cells. Dysregulation of cell fate specification and differentiation leads to various diseases, yet the cellular and molecular mechanisms governing these processes remain elusive. We demonstrate that YAP/TAZ activation reprograms airway secretory cells, which subsequently lose their cellular identity and acquire squamous alveolar type 1 (AT1) fate
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The needs of a synapse-How local organelles serve synaptic proteostasis. EMBO J. (IF 11.598) Pub Date : 2022-03-14 Katarzyna M Grochowska,Maria Andres-Alonso,Anna Karpova,Michael R Kreutz
Synaptic function crucially relies on the constant supply and removal of neuronal membranes. The morphological complexity of neurons poses a significant challenge for neuronal protein transport since the machineries for protein synthesis and degradation are mainly localized in the cell soma. In response to this unique challenge, local micro-secretory systems have evolved that are adapted to the requirements
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Fast co-evolution of anti-silencing systems shapes the invasiveness of Mu-like DNA transposons in eudicots. EMBO J. (IF 11.598) Pub Date : 2022-03-14 Taku Sasaki,Kyudo Ro,Erwann Caillieux,Riku Manabe,Grégoire Bohl-Viallefond,Pierre Baduel,Vincent Colot,Tetsuji Kakutani,Leandro Quadrana
Transposable elements (TEs) constitute a major threat to genome stability and are therefore typically silenced by epigenetic mechanisms. In response, some TEs have evolved counteracting systems to suppress epigenetic silencing. In the model plant Arabidopsis thaliana, two such anti-silencing systems have been identified and found to be mediated by the VANC DNA-binding proteins encoded by VANDAL transposons
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HOIL-1 ubiquitin ligase activity targets unbranched glucosaccharides and is required to prevent polyglucosan accumulation. EMBO J. (IF 11.598) Pub Date : 2022-03-11 Ian R Kelsall,Elisha H McCrory,Yingqi Xu,Cheryl L Scudamore,Sambit K Nanda,Paula Mancebo-Gamella,Nicola T Wood,Axel Knebel,Stephen J Matthews,Philip Cohen
HOIL-1, a component of the linear ubiquitin chain assembly complex (LUBAC), ubiquitylates serine and threonine residues in proteins by esterification. Here, we report that mice expressing an E3 ligase-inactive HOIL-1[C458S] mutant accumulate polyglucosan in brain, heart and other organs, indicating that HOIL-1's E3 ligase activity is essential to prevent these toxic polysaccharide deposits from accumulating
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Stem cells "aclymatise" to regenerate the blood system. EMBO J. (IF 11.598) Pub Date : 2022-03-11 Livia E Lisi-Vega,Simón Méndez-Ferrer
How blood stem cells balance fate decisions between quiescence maintenance and differentiation during recovery from cancer treatment remains poorly understood. A recent study by Umemoto et al (2022) uncovers an unexpected linkage between metabolic and epigenetic regulation of haematopoiesis, suggesting new targets in haematopoietic regeneration, with possible implications in leukaemogenesis and therapy
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Keratin filaments mediate the expansion of extra-embryonic membranes in the post-gastrulation mouse embryo. EMBO J. (IF 11.598) Pub Date : 2022-03-10 Wallis Nahaboo,Sema Elif Eski,Evangéline Despin-Guitard,Marjorie Vermeersch,Marie Versaevel,Bechara Saykali,Daniel Monteyne,Sylvain Gabriele,Thomas M Magin,Nicole Schwarz,Rudolf E Leube,An Zwijsen,David Perez-Morga,Sumeet Pal Singh,Isabelle Migeotte
Mesoderm arises at gastrulation and contributes to both the mouse embryo proper and its extra-embryonic membranes. Two-photon live imaging of embryos bearing a keratin reporter allowed recording filament nucleation and elongation in the extra-embryonic region. Upon separation of amniotic and exocoelomic cavities, keratin 8 formed apical cables co-aligned across multiple cells in the amnion, allantois
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Autophagy-mediated plasma membrane removal promotes the formation of epithelial syncytia. EMBO J. (IF 11.598) Pub Date : 2022-03-09 Parisa Kakanj,Sourabh Bhide,Bernard Moussian,Maria Leptin
Epithelial wound healing in Drosophila involves the formation of multinucleate cells surrounding the wound. We show that autophagy, a cellular degradation process often deployed in stress responses, is required for the formation of a multinucleated syncytium during wound healing, and that autophagosomes that appear near the wound edge acquire plasma membrane markers. In addition, uncontrolled autophagy
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Ageing induces tissue-specific transcriptomic changes in Caenorhabditis elegans. EMBO J. (IF 11.598) Pub Date : 2022-03-07 Xueqing Wang,Quanlong Jiang,Yuanyuan Song,Zhidong He,Hongdao Zhang,Mengjiao Song,Xiaona Zhang,Yumin Dai,Oezlem Karalay,Christoph Dieterich,Adam Antebi,Ligang Wu,Jing-Dong J Han,Yidong Shen
Ageing is a complex process with common and distinct features across tissues. Unveiling the underlying processes driving ageing in individual tissues is indispensable to decipher the mechanisms of organismal longevity. Caenorhabditis elegans is a well-established model organism that has spearheaded ageing research with the discovery of numerous genetic pathways controlling its lifespan. However, it
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Endothelium-derived lactate is required for pericyte function and blood-brain barrier maintenance. EMBO J. (IF 11.598) Pub Date : 2022-03-03 Heon-Woo Lee,Yanying Xu,Xiaolong Zhu,Cholsoon Jang,Woosoung Choi,Hosung Bae,Weiwei Wang,Liqun He,Suk-Won Jin,Zoltan Arany,Michael Simons
Endothelial cells differ from other cell types responsible for the formation of the vascular wall in their unusual reliance on glycolysis for most energy needs, which results in extensive production of lactate. We find that endothelium-derived lactate is taken up by pericytes, and contributes substantially to pericyte metabolism including energy generation and amino acid biosynthesis. Endothelial-pericyte
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ATP citrate lyase controls hematopoietic stem cell fate and supports bone marrow regeneration. EMBO J. (IF 11.598) Pub Date : 2022-03-01 Terumasa Umemoto,Alban Johansson,Shah Adil Ishtiyaq Ahmad,Michihiro Hashimoto,Sho Kubota,Kenta Kikuchi,Haruki Odaka,Takumi Era,Daisuke Kurotaki,Goro Sashida,Toshio Suda
In order to support bone marrow regeneration after myeloablation, hematopoietic stem cells (HSCs) actively divide to provide both stem and progenitor cells. However, the mechanisms regulating HSC function and cell fate choice during hematopoietic recovery remain unclear. We herein provide novel insights into HSC regulation during regeneration by focusing on mitochondrial metabolism and ATP citrate